Chronic neuropathic pain syndromes including craniofacial and dental pain syndromes represent large unmet medical needs and are inadequately treated with current drugs. Conversion from acute pain to chronic neuropathic pain syndromes may result from maladaptive changes in the peripheral and central somatosensory system in reaction to the initial tissue injury that caused the acute pain. This project proposes t generate new knowledge on the basic pathophysiology chronic neuropathic pain by determining the genetic differences between patients who develop chronic neuropathic pain after initial tissue injury versus those who do not despite having the same acute tissue injury. We propose here to leverage the unique genetic resources gathered and developed at deCODE Genetics for whole genome sequence-based human pain genetics studies to uncover high risk variants of low frequency significantly associated to conversion from acute to chronic pain. In this project, we propose to extensively re-phenotype large cohorts with chronic neuropathic pain including common forms of craniofacial pain. We already have lists of Icelandic patients who have or are likely to have certain chronic neuropathic pain syndromes totaling over 12,000 patients. We will study large cohorts of phantom tooth pain (persistent dento-alveolar pain (PDAP)), temporomandibular disorder (TMD), and post-mastectomy pain syndrome. We will also screen a large cohort of Icelanders taking gabapentin or pregabalin for common chronic pain syndromes including diabetic neuropathy and post-herpetic neuralgia. The extra phenotyping will give us additional dimensions beyond the basic pain symptomology including quality and intensity on which to condition the genetic analysis. It may also make it easier to replicate our findings in outside pain cohorts that have already been well-phenotyped by our collaborators. We can generate whole genome sequences for large cohorts of pain syndromes and controls in Iceland more quickly and cost-effectively than in other populations. Although costs are dropping rapidly, it is still very expensive to fully sequence the genomes of the thousands of individuals that are required for well-powered disease association studies. We leverage our genealogy database and high density DNA chip data to propagate all genomic variation down to rare allelic frequencies of 0.05% from thousands of fully sequenced Icelanders to over one hundred thousand Icelanders. Using these full sequences and by sequencing the whole-genomes of 150 individuals from families with a high prevalence of either PDAP or TMD, we plan to perform whole-genome association studies of chronic neuropathic pain syndromes with large effective sample sizes, studies that would otherwise be prohibitively costly. We expect to find many new genetic associations that will increase our understanding of conversion from acute to chronic neuropathic pain syndromes. The primary data generated in this grant will be made widely available for others to build on. PUBLIC HEALTH RELEVANCE: Chronic neuropathic pain syndromes are common and costly public health problems leading to disability, suffering, and addiction to opiates. Understanding the genetic basis for why some patients develop chronic neuropathic pain syndromes while others do not after oral surgery or surgeries for breast cancer or cardiac disease may reveal key molecular pathways that may lead to more efficacious and non-addicting drugs for chronic pain. We will also study other common neuropathic pain syndromes and temporomandibular disorders. We plan to leverage our ongoing sequencing program to compare full genome sequences of individuals developing chronic pain syndromes with patients who do not develop pain after the same initial acute tissue injury such as surgery.